Prophylactic pegfilgrastim reduces febrile neutropenia in ramucirumab plus docetaxel after chemoimmunotherapy in advanced NSCLC: post hoc analysis from NEJ051

Ramucirumab plus docetaxel (RD) can cause febrile neutropenia (FN), which frequently requires the prophylactic administration of pegfilgrastim. However, the effects of prophylactic pegfilgrastim on FN prevention, therapeutic efficacy, and prognosis after RD have not been fully evaluated in patients with advanced non-small-cell lung cancer (NSCLC). Two hundred and eighty-eight patients with advanced NSCLC who received RD as second-line therapy after platinum-based chemotherapy plus PD-1 blockade were included. Patients were divided into groups with and without prophylactic pegfilgrastim, and adverse events, efficacy, and prognosis were compared between both groups. Of the 288 patients, 247 received prophylactic pegfilgrastim and 41 did not. The frequency of grade 3/4 neutropenia was 62 patients (25.1%) in the pegfilgrastim group and 28 (68.3%) in the control group (p < 0.001). The frequency of FN was 25 patients (10.1%) in the pegfilgrastim group and 10 (24.4%) in the control group (p = 0.018). The objective response rate was 31.2% and 14.6% in the pegfilgrastim and control groups (p = 0.039), respectively. The disease control rate was 72.9% in the pegfilgrastim group and 51.2% in the control group (p = 0.009). Median progression free survival was 4.3 months in the pegfilgrastim group and 2.5 months in the control group (p = 0.002). The median overall survival was 12.8 and 8.1 months in the pegfilgrastim and control groups (p = 0.004), respectively. Prophylactic pegfilgrastim for RD reduced the frequency of grade 3/4 neutropenia and febrile neutropenia and did not appear to be detrimental to patient outcome RD. Clinical Trial Registration Number: UMIN000042333.


Patient demographics
Table 1 shows the demographics of patients classified according to the presence or absence of PEG treatment.Two hundred and forty-seven patients (85.8%) received prophylactic PEG treatment, and 41 (14.2%) (control group) did not.The number of patients with a history of smoking was significantly higher in the control group than in the PEG group (p = 0.025).There were no significant differences in other factors.Of the 247 patients with PEG prophylaxis, 223 (90.3%) underwent prophylaxis during the first cycle of RD and 24 (9.7%) during the second cycle.Therefore 65 patients (41 control plus 24 s cycle) did not receive PEG prophylaxis during the first cycle of RD.Table 2 shows the characteristics of the patients who did/did not receive PEG prophylaxis during the first cycle.The proportion of patients aged ≥ 75 years was significantly higher in the PEG than in the control group Table 1.Comparison of patient characteristics with or without pegfilgrastim.yrs, years; PEG, pegfilgrastim; AC, adenocarcinoma; Ope rec., recurrence after operation; RT, radiation therapy; TPS, tumor proportion score; PD-L1, programmed death-ligand 1; UN, unknown; PD-L1, programmed death-ligand 1; bold character, statistical significance.*At the beginning of first-line therapy.

Implementation status of drug delivery
The starting dose of docetaxel for RD was 60 mg/m 2 in 270 (93.8%) patients and < 60 mg/m 2 in 18 (6.3%)patients.
Of the 247 patients with PEG prophylaxis, the docetaxel dose was 60 mg/m 2 in 233 (94.3%) and < 60 mg/m 2 in 14 (5.7%).Of the 41 controls, the docetaxel dose was 60 mg/m 2 in 37 (90.2%) and < 60 mg/m 2 in 4 (9.8%)patients.The median number of RD cycles in all patients was 4 (range, 1-22).The median number of RD cycles with and without PEG prophylaxis was

Survival analysis
Figure

Relationship between first-line treatment and RD
The PFS (175 days vs. 167 days, p = 0.095) and ORR (55.1% vs. 43.9%,p = 0.236) to first-line treatments were not significantly different between the patients who used and did not use PEG.Moreover, the response of PR or CR to first-line treatments was observed in 54 (70.1%) of 77 patients and 4 (66.7%) of 6 patients with CR or PR to RD in the PEG group and control group, respectively, without statistical significance.

Adverse events
Table 4 shows hematological toxicities.The frequencies of grade 3/4 leukopenia, anemia, thrombocytopenia, neutropenia, and FN in all patients were 23.6%, 6.3%, 2.1%, 31.3%, and 12.2%, respectively.The frequencies of grade 3/4 leukopenia were 21.5% in the PEG prophylaxis group and 36.6% in the control group (p = 0.046), those of grade 3/4 neutropenia were 25.1% in the PEG group and 68.3% in the control group (p < 0.001), and those of FN were 10.1% in the PEG prophylaxis group and 24.4% in the control group (p = 0.018).No statistically significant differences were observed in the non-hematological AE between the PEG and control groups (Table 5).

Discussion
This post-hoc analysis identified the clinical usefulness of prophylactic PEG in patients with advanced NSCLC who received RD immediately after PD-1 blockade plus platinum-based chemotherapy.We found that the frequency of FN was 10.1% in the PEG prophylaxis group and 24.4% in the control group.The incidence of FN in the REVEL and JVCG studies was 16% and 34.2%, respectively 1,3 .The incidence of FN in patients who underwent prophylactic PEG in our study was lower than that reported in previous prospective studies 1,3 .Although 3 months (95% CI 3.9-4.8) in the PEG prophylaxis group and 2.5 months (95% CI 1.1-3.9) in the control group (p = 0.002).Median overall survival was 12.8 months (95% CI 10.7-14.9) in the PEG prophylaxis group and 8.1 months (95% CI 5.0-11.2) in the control group (p = 0.004).Several studies have described the palliative usefulness of RD treatment for FN prevention 5,[7][8][9][10][11] .When prophylactic PEG was administered for RD treatment, the incidence of FN was < 10%, with an average of approximately 5% 5,[7][8][9][10][11] .Without prophylactic PEG, the incidence of FN was approximately 25% 7,8,10,11 .Considering the results of previous and current studies, prophylactic PEG immediately after RD treatment should be considered routinely necessary for the prevention of FN and the continuous administration of RD.A retrospective study has reported that the prophylactic use of PEG reduced the hospitalization rate for multiple cancer types 12 .In our study, the number of dosing cycles of RD tended to be higher in the PEG group, although the frequency of discontinuation due to AE or progressive disease was similar in the PEG prophylaxis and PEG control groups.The optimal timing for chemotherapeutic administration of prophylactic PEG may affect the efficacy and prognosis of RD treatment.Mouri et al. compared the efficacy and outcome of RD between 29 patients with PEG prophylaxis and 4 patients without 8 .Because of the very small size of the control group, the ORR, PFS, and OS were not significantly different between the two groups.Moreover, Sakaguchi et al. reported that 95 of their 114 (83.3%) patients received prophylactic PEG, whereas 19 (16.7%) did not 9 .Although their study did not include information regarding the incidence of FN in the control group, the use of prophylactic PEG was significantly associated with favorable PFS and OS 9 .However, there are several concerns about previous studies.The number and regimens of prior treatments before RD initiation differed in each study, and there was no uniformity in prior immune checkpoint inhibitor (ICI) treatment.A recent study suggested the potential for increased efficacy of RD by prior ICI treatment 13 .Considering the regimens used in previous studies 8,9 , prior immunotherapy may affect the therapeutic efficacy of RD treatment, regardless of the administration of prophylactic PEG.In our study, the regimen administered just before RD was unified as PD-1 blockade plus platinum-based chemotherapy.Interestingly, we found that prophylactic PEG affected the therapeutic efficacy of RD immediately after chemoimmunotherapy.A recent preclinical study demonstrated that PEG enhances the antitumor activity of immunotherapy with antibody-dependent cellular cytotoxicity (ADCC) or phagocytosis (ADCP) 14 .As a possible mechanism, stimulation with PEG was related to significant enhancement of leukocytes in the spleen and the mobilization of activated monocytes or granulocytes from the spleen to the tumor bed 14 .Although it remains unknown whether PEG could potentiate the antitumor activity of PD-1 blockade, the synergistic relationship between PEG and prior immunotherapy is an interesting topic requiring further investigation to elucidate a possible mechanism.Currently, immunotherapy or chemoimmunotherapy are the standard first-line treatments for the care of patients with advanced NSCLC.Unlike previous studies, our study included all patients receiving first-line chemoimmunotherapy.Therefore, our population size meets the requirements for actual clinical practice and will be helpful to physicians.
A new device for convenient PEG administration has been developed.An on-body injector (OBI) is a device worn by patients after chemotherapy that automatically administers PEG approximately 27 h later 15 .OBI was not inferior to conventional manual injection in terms of pharmacokinetic safety 15 .Prospective studies in breast cancer, prostate cancer, lung cancer, and non-Hodgkin's lymphoma have reported that the OBI reduces neutropenia compared with conventional FN strategies 16 .The use of the OBI has been suggested to improve adherence and compliance.Thus, preventive effects of the OBI on FN are expected in patients with cancer receiving strong myelosuppressive chemotherapy.
This study has limitations.First, the number of patients in the PEG (n = 247) and control groups (n = 41) was unbalanced because of a retrospective sub-analysis.Second, we could not determine the reasons for choosing PEG, as the decision to use prophylactic PEG depended on the physicians at each institution.An imbalance in the patients in each group may have affected the results of our study.This difference between the PEG prophylaxis and control groups may be associated with differences in efficacy and outcomes of RD treatment.Finally, we could not collect information on whether patients had undergone filgrastim treatment at neutropenia or FN onset in the control group.Future prospective comparative studies are required to verify the therapeutic efficacy and outcomes of PEG prophylaxis in RD treatment.This study is a retrospective assessment, and the major difference between the patients who received and did not receive PEG depended on the judgment of chief physicians at different institutions.No precious definition of PEG administration remains unclear, thus, it may bias the results of our study.
Prophylactic PEG for RD therapy significantly reduced the frequency of neutropenia and FN in patients with advanced NSCLC after chemotherapy.The use of prophylactic PEG does not appear to be detrimental to patient outcome of RD in such patients.Prophylactic PEG is clinically recommended for the prevention of FN after RD.

Design
A total of 62 Japanese institutions participated in this post-hoc analysis (OnlineAppendix Table S1).We identified 288 patients who received RD as second-line therapy after first-line platinum-based chemotherapy plus PD-1 blockade therapy between January 2017 and August 2020.Our analysis was performed using the same sample as that used in a previously described study 2 .The following were administered as first-line treatments: • Pembrolizumab plus cisplatin or carboplatin plus pemetrexed therapy (KEYNOTE-189) 17 ; • Pembrolizumab plus carboplatin plus nab-paclitaxel or paclitaxel therapy (KEYNOTE-407) 18 ; • Atezolizumab plus carboplatin plus paclitaxel plus bevacizumab therapy (IMpower150) 19 ; • Atezolizumab plus carboplatin plus nab-paclitaxel therapy (IMpower130) 20 ; or • Atezolizumab plus carboplatin plus pemetrexed therapy (IMpower132) 21 .
Patients who received PEG prophylaxis after RD initiation were compared with those who did not.Clinical data up to March 31, 2021, were extracted from the medical records.This study was approved by the institutional ethics committees of Saitama Medical University International Medical Center.The requirement for informed consent was waived by the ethics committee of the Saitama Medical University International Medical Center owing to the retrospective nature of the study.We would like to confirm that all procedures and methodologies used in this study were carried out in strict compliance with the relevant guidelines and regulations as stipulated by the journal's editorial policy.We have obtained all required permissions and have ensured that our methods are transparent, ethical, and rigorous.

Treatment and evaluation
All patients received combined chemotherapy with anti-PD-1/PD-L1 antibodies as first-line treatment.The KEYNOTE-189 17 , KEYNOTE-407 18 , IMpower150 19 , IMpower130 20 , and IMpower132 regimens 21 were intravenously administered.RD (ramucirumab 10 mg/kg and docetaxel 60 mg/m 2 ) was intravenously administered as second-line treatment.PEG (3.6 mg, G-LASTA™, Kyowa Kirin Co. Ltd., Tokyo, Japan), a prophylactic granulocyte colony-stimulating factor used after RD initiation, was administered based on the judgement of the chief doctor at the individual institution, and its subcutaneous administration was performed per chemotherapy cycle in all patients.
Physical examinations, complete blood counts, biochemical tests, and the recording of adverse events (AE) were performed at the discretion of the chief physicians at the respective institutions.Toxicity was graded based on the Common Terminology Criteria for Adverse Events, version 4.0.The tumor response was examined according to the Response Evaluation Criteria in Solid Tumors version 1.1. 22.

Prognostic endpoints' definition
The periods considered for overall survival (OS) versus progression free survival (PFS) events were as follows: initiation of RD till the date of mortality due to any cause versus initiation of RD till the dates of exacerbation or mortality due to any cause, or initiation of third-line treatment.

Statistics
To summarize the patient background and treatment results, we calculated the number of patients in each category and the median and maximum values in the continuous data.We further calculated the objective response rate (ORR) and disease control rate (DCR); [%, 95% CI].The Kaplan-Meier method was used to obtain the survival curves.The significance levels of the tests and confidence coefficients for interval estimation were 5% and 95%, respectively, on both sides.Fisher's exact test was used to examine the association between categorical variables.GraphPad Prism (version 7.0; GraphPad Software, San Diego, CA, USA) and JMP 14.0 (SAS Institute Inc., Cary, North Carolina, USA) were used for statistical analyses.
The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Keita Miura reports a relationship with Chugai Pharmaceutical Co Ltd that includes speaking and lecture fees.Keita Miura reports a relationship with Taiho Pharmaceutical Co Ltd that includes speaking and lecture fees.Kentaro Ito reports a relationship with Eli Lilly that includes speaking and lecture fees.Kentaro Ito reports a relationship with Boehringer Ingelheim that includes speaking and lecture fees.Kentaro

288) PEG Yes (n = 247) No (n = 41) p-value
the first cycle among the different histology.The PFS was not significantly different between the PEG prophylaxis and control groups in AC patients, but a statistically significant difference was observed between groups in PFS and OS for non-AC patients and OS for AC patients.
Vol.:(0123456789) Scientific Reports | (2024) 14:3816 | https://doi.org/10.1038/s41598-024-54166-xwww.nature.com/scientificreports/there were no significant differences in the patient characteristics between the two groups, prophylactic PEG potentially improved compliance with RD administration by preventing the occurrence of FN.Our large-scale study confirmed that prophylactic PEG can improve the therapeutic efficacy and minimize the toxicity of RD treatment after first line chemoimmunotherapy.However, we guess that the different incidence of FN between

Table 5 .
Non-hematological toxicities of ramucirumab plus docetaxel.PEG, pegfilgrastim; AST, aspartate aminotransferase; ALT, alanine aminotransferase.JVCG and REVEL study may be caused by the ethnic different between Caucasian and Asian patients.Therefore, we should recommend the use of prophylactic PEG only to Asian patients.
Vol:.(1234567890) Scientific Reports | (2024) 14:3816 | https://doi.org/10.1038/s41598-024-54166-xwww.nature.com/scientificreports/ Ito reports a relationship with Takeda Pharmaceutical Co Ltd that includes speaking and lecture fees.Kentaro Ito reports a relationship with Chugai Pharmaceutical Co Ltd that includes speaking and lecture fees.Kentaro Ito reports a relationship with Pfizer that includes speaking and lecture fees.Kentaro Ito reports a relationship with Merck & Co Inc. that includes speaking and lecture fees.Kentaro Ito reports a relationship with AstraZeneca that includes speaking and lecture fees.Kentaro Ito reports a relationship with Ono Pharmaceutical Co Ltd that includes speaking and lecture fees.Kentaro Ito reports a relationship with Taiho Pharmaceutical Co Ltd that includes speaking and lecture fees.Daisuke Arai reports a relationship with Chugai Pharmaceutical Co Ltd that includes speaking and lecture fees.Daisuke Arai reports a relationship with AstraZeneka KK Tokyo Branch that includes speaking and lecture fees.Daisuke Arai reports a relationship with Ono Pharmaceutical Co Ltd that includes speaking and lecture fees.Daisuke Arai reports a relationship with Taiho Pharmaceutical Co Ltd that includes speaking and lecture fees.Daisuke Arai reports a relationship with Takeda Pharmaceutical Co Ltd that includes speaking and lecture fees.Daisuke Arai reports a relationship with Nippon Kayaku Co Ltd that includes speaking and lecture fees.Daisuke Arai reports a relationship with Merck & Co Inc that includes speaking and lecture fees.Kyoichi Kaira reports financial support was provided by Eli Lilly Japan KK. Kyoichi Kaira reports a relationship with AstraZeneca Pharmaceuticals LP that includes speaking and lecture fees.Hiroaki Kodama reports a relationship with Chugai Pharmaceutical Co Ltd that includes speaking and lecture fees.Hiroaki Kodama reports a relationship with Boehringer Ingelheim Pharmaceuticals Inc that includes speaking and lecture fees.Hiroaki Kodama reports a relationship with Novartis Pharmaceuticals Corporation that includes speaking and lecture fees.Kunihiko Kobayashi reports a relationship with AstraZeneca that includes speaking and lecture fees.Kunihiko Kobayashi reports a relationship with Takeda Pharmaceutical Co Ltd that includes speaking and lecture fees.Atsushi Nakamura reports a relationship with MSD that includes speaking and lecture .Atsushi Nakamura reports a relationship with Thermo Fisher Scientific that includes speaking and lecture fees.Atsushi Nakamura reports a relationship with AstraZeneca that includes speaking and lecture fees.Atsushi Nakamura reports a relationship with Eli Lilly Japan KK that includes speaking and lecture fees.Atsushi Nakamura reports a relationship with Chugai Pharmaceutical Co Ltd that includes speaking and lecture fees.Atsushi Nakamura reports a relationship with Taiho Pharmaceutical Co Ltd that includes speaking and lecture fees.Atsushi Nakamura reports a relationship with Nippon Kayaku Co Ltd that includes speaking and lecture fees.Atsushi Nakamura reports a relationship with Novartis Pharma that includes speaking and lecture fees.Takashi Ninomiya reports a relationship with Boehringer Ingelheim that includes speaking and lecture fees.Takashi Ninomiya reports a relationship with AstraZeneca that includes speaking and lecture fees.Takashi Ninomiya reports a relationship with Chugai Pharmaceutical Co Ltd that includes speaking and lecture fees.Ou Yamaguchi reports a relationship with Eli Lilly Japan K.K. that includes speaking and lecture fees.Ou Yamaguchi reports a relationship with Ono Pharmaceutical Co Ltd that includes speaking and lecture fees.Ou Yamaguchi reports a relationship with Bristol Myers Squibb Co that includes speaking and lecture fees.Ou Yamaguchi reports a relationship with Chugai Pharmaceutical Co Ltd that includes speaking and lecture fees.Ou Yamaguchi reports a relationship with Merck Sharp & Dohme Corp that includes speaking and lecture fees.Ou Yamaguchi reports a relationship with AstraZeneca that includes speaking and lecture fees.Noriko Yanagitani reports a relationship with Chugai Pharmaceutical Co Ltd that includes speaking and lecture fees.Noriko Yanagitani reports a relationshipwith Ono Pharmaceutical Co Ltd that includes speaking and lecture fees.Noriko Yanagitani reports a relationship with Bristol Myers Squibb that includes speaking and lecture fees.Noriko Yanagitani reports a relationship with Pfizer Inc that includes speaking and lecture fees.Noriko Yanagitani reports a relationship with Takeda Pharmaceutical Company Limited that includes speaking and lecture fees.Noriko Yanagitani reports a relationship with Eli Lilly and Company that includes speaking and lecture fees.Noriko Yanagitani reports a relationship with AstraZeneca PLC that includes speaking and lecture fees.Noriko Yanagitani reports a relationship with Bayer Holding Co Ltd that includes speaking and lecture fees.Noriko Yanagitani reports a relationship with Chugai Pharmaceutical Co Ltd that includes paid expert testimony.All other Authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.